Clopidogrel is an inhibitor of platelet aggregation. Clopidogrel's platelet inhibiting activity makes it an effective drug for reducing the induce of ischemic strokes or heart attacks. By inhibiting platelet aggregation, Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks. Recent studies have shown that Clopidogrel is more effective in blocking platelet aggregation than Aspirin. Clopidogrel is much effective than Aspirin even at much lower dosage. In addition to being more effective, Clopidogrel produces much less gastrointestinal bleeding than Aspirin.
European patent 281459 describes the enantiomers of tetrahydrothieno pyridine derivatives and their pharmaceutically acceptable salts. The patent specifically claims Clopidogrel hydrogen sulfate, i.e., the dextrorotatory isomer which posses an excellent platelet aggregation inhibiting activity whereas the levo-rotatory isomer is less active. EP 281459 makes no reference to existence of the specific polymorphic forms of clopidigrel hydrogen sulfate.
Dextro-rotatory isomer of Clopidogrel is prepared by salt formation from the racemic compound using an optically active acid such as 10-L-camphorsulphonic acid in acetone, followed by successive re-crystallization of the salt until a product with constant rotatory power is obtained, followed by release of dextro-rotatory, isomer from its salt by a base. Clopidogrel hydrogen sulfate is then obtained in standard manner by the dissolution of said base in acetone cooled in ice and addition of concentrated sulfuric acid to precipitation. The precipitate thus obtained is then isolated by filtration, washed and dried to give Clopidogrel hydrogen sulfate in the form of white crystals. U.S. Pat. Nos. 4,874,265; 5,132,435; 6,258,961, 6,215,005 and 6,180,793 describe methods that can be used to prepare Clopidogrel hydrogen sulfate.
Clopidogrel bisulfate Form I and II was first time disclosed in International Publication No. WO 99/65915, though Form-I is originally disclosed in EP 281459. U.S. Pat. Nos. 6,429,210; 6,504,030 and US patent application 2002/019829 A1 disclose the manufacturing process of Clopidogrel hydrogen sulfate Form-I and II. These polymorphs are prepared by dissolving Clopidogrel camphor sulfate in acetone followed by addition of conc. Sulfuric acid at an ambient temperature. Excess of acetone is distilled and residue is cooled down to 0-5° C. followed by filtration to get Clopidogrel Form-I. The Form-II of Clopidogrel is obtained from residual mother liquor after 3-6 months period. These US patents does not disclose a process for the manufacture of Form-I only and hence, there is huge loss in the yield of Clopidogrel hydrogen sulfate Form-I. US patent application 2003/0114479 discloses the manufacturing processes for Clopidogrel hydrogen sulfate Form-I, II, III, IV, V and amorphous forms. The application also claims the preparation of Clopidogrel hydrogen sulfate Form-I from amorphous Clopidogrel hydrogen sulfate. Specification of the US patent application 2003/0114479 discloses the preparation method of Clopidogrel hydrogen sulfate Form-I using different combinations of alcohol and ether in 56-88% yield.